It is well-documented that testosterone therapy effectively restores testosterone levels in hypogonadal men and improves many health outcomes, such as quality of life 1-4, libido 4,5, metabolic parameters 5-9 and body composition.4,5,9,10

However, a few conflicting studies raised concerns about the cardiovascular safety of testosterone therapy 11,12, which in 2015 prompted the FDA to issue warnings to physicians and patients about potential cardiovascular risks of testosterone therapy. In contrast, the European Medicines Agency (EMA) acknowledged the flaws of the conflicting studies and concluded that there is no consistent evidence of harm associated with testosterone therapy, regardless of mode of delivery.13

Here we present the cardiovascular results of the notable RHYME (The Registry of Hypogonadism in Men) study, which contrary to prior clinical trials, enrolled patients with a wide range of comorbid illnesses and cardiovascular risk factors.14 The aim was to evaluate the safety of testosterone therapy in a sufficiently diverse population to reflect real-world, clinical experience.14

Key Points

In comparison to both untreated men and to age-matched population data, no increase in mortality or cardiovascular risk was observed with testosterone therapy, regardless of:

What is known

The EMA conclusion is supported by the latest testosterone therapy guidelines from the European Association of Urology (EAU) 15, International Society for Sexual Medicine (ISSM) 16, European Menopause Andropause Society (EMAS) 17, Canadian Men's Health Foundation 18 and the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE).19

What this study adds

The RHYME study was a multi-national, longitudinal disease registry of men diagnosed with hypogonadism at 25 clinical sites in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2-3 years. Independent adjudication was performed on all mortalities and cardiovascular outcomes.

Of 999 patients enrolled with clinically diagnosed hypogonadism, 750 (75%) initiated some form of testosterone therapy. Registry participants, including both treated and untreated patients, contributed 23 900 person-months follow-up time. A total of 55 reported cardiovascular events occurred in 41 patients. Overall, five patients died of cardiovascular -related causes (3 on testosterone therapy, 2 untreated) and none of the deaths were adjudicated as treatment-related. The overall cardiovascular incidence rate was 1522 per 100 000 person-years. Cardiovascular event rates for men receiving testosterone therapy were not statistically different from untreated men.

Regardless of treatment assignment, cardiovascular event rates were higher in older men and in those with increased cardiovascular risk factors or a prior history of cardiovascular events.

Commentary

The RHYME study was designed and conducted by an independent research organisation (New England Research Institutes) as the first stage in a planned multi-national programme of long-term studies of testosterone therapy.29 It is notable in that it enrolled a diverse population reflective of real-world, clinical experience, and subjects were systematically monitored for up to 36 months, a substantially longer period of follow-up compared to recent RCT’s.20,30 The independent adjudication of all mortalities and cardiovascular outcomes is a strength of this study, as a previous study which alluded to increased cardiovascular events included trivial outcomes, such as syncope.30 This study found that predictors of new-onset cardiovascular events in this multi-national, prospective hypogonadism registry were age and prior cardiovascular history, not testosterone use.

The conclusion that testosterone therapy - regardless of the type of testosterone administered – does not increase mortality or cardiovascular risk, compared to both untreated men and to age-matched population data, is reassuring. This is the first large cohort study of hypogonadal men that includes sizable samples of men with both primary and secondary hypogonadism, neither of which showed an increase in cardiovascular events with testosterone therapy.

This lack of association between testosterone use and cardiovascular-related adverse events was evident in both younger and older hypogonadal men, regardless of the type of hypogonadism being treated (primary vs. secondary) or mode of testosterone administration (injectable vs. topical preparations). None of the cardiovascular-related mortalities were judged to be related to testosterone therapy, but were significantly associated with prior or current cardiovascular conditions. These results are consistent with results from other patient registries in the US 25,26 and Europe 7,31-33 showing relative safety of testosterone therapy in hypogonadal men with multiple comorbid illnesses and cardiovascular risk factors.

Despite FDA’s specific labelling caution for potential risks of deep vein thrombosis with testosterone therapy 34, this recommendation is not supported by results from recent studies, such as a large-scale medical record database review 24 , the T-Trial 20, and the current findings in RHYME (presented here).14